| Abstract: | Cholesterol homeostasis in animal cells is attained by balancing extracellular cholesterol uptake through low density lipoprotein receptors (LDLr) with de novo intracellular cholesterol biosynthesis. Maintaining appropriate cholesterol levels is critical for health as high levels can lead to atherosclerosis. Individuals with high cholesterol levels are currently treated with HMG-CoA reductase inhibitors that prevent cholesterol biosynthesis and increase production of LDLr, allowing increased uptake of cholesterol from plasma. However, direct up-regulation of LDLr synthesis would lead to the lowering of LDL cholesterol and could provide an alternative treatment for hypercholesterolaemia and provide additional benefit for those not adequately treated by statins. This article reviews compounds that increase LDLr activity by mechanisms that are postulated to have a direct effect at stimulating LDLr gene expression and not secondary effects as a consequence of inhibiting cholesterol biosynthesis. The mechanisms by which these compounds stimulate LDLr activity are novel and their interactions at the molecular level remain to be elucidated. Detailed understanding of these interactions and other factors involved in the regulation of the LDLr gene holds great promise for the discovery of superior agents for the treatment of hypercholesterolaemia |
